PROPOSED PROGRAM (Adapted from Applicant's Abstract) The objectives of this application, Ion Channels and the Therapy of Ventricular Arrhythmias, are to identify the changes in ion channel function that occur as a consequence of prolonged cardiac ischemia and infraction (ion channel remodeling), some of the molecular mechanisms that cause these changes, how ion channel remodeling causes ventricular arrhythmias and how the remodeled ion channel function can be modified by drugs to provide anti-arrhythmic effects. The Program consists of four highly integrated Projects: 'Remodeling of Gap Junctions in Reentrant Circuits', Dr. Andrew L. Wit, Project Leader, and Molecular the consequences of remodeling of gap junctions and how they lead to slow conduction, block and reentrant excitation. The structural features of gap junctional remodeling will be investigated with immunofluorescent techniques, the electrophysiological alterations with mapping and patch clamp studies of myocyte cell pairs. The molecular mechanisms will be studied in the infarcted canine heart and transgenic murine models. "Ion Channel Function in Myocardial Cells from Infarcts," Dr. Penelope Boyden, Project Leader and "Molecular Targeting of Ca2+ and K+ Channels in Heart," Dr. Robert Kass, Project Leader, focus on sarcolemmal ion channel remodeling. Dr. Boyden's project channels will characterize the electrophysiological changes in Na+, Ca2+ and K+ channels in infarct border zone myocytes, defining the heterogeneity remodeling in different parts of reentrant pathways and how it effects drug action. The last project, Ca2+ and K+ channels expressed in mammalian systems in which subunits can be varied, serve as models to investigate the actions of anti-arrhythmic drugs, particularly the molecular basis of action of L-type calcium agonist shown to stop reentrant excitation. The project will also focus on how remodeling of the delayed rectified K+ current alters drug action, particularly the molecular basis of action of an L-type calcium agonist shown to stop reentrant excitation. The project will also focus on how remodeling of the delayed rectified K+ current alters drug action. These Projects are supported by an administrative unit (Core A), an electronics and computer Core, and Core C which provides dissociated remodeled ion channels in causing arrhythmias and provide the necessary remodeled channels and prevent sudden cardiac death.